chr1-196774939-G-C

Position:

• chr1-196774939-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_021023.6(CFHR3):​c.53G>C​(p.Gly18Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,526,620 control chromosomes in the GnomAD database, including 894 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (44 hom., cov: 25)
  • Exomes 𝑓: 0.0034 (850 hom.)
• Consequence: CFHR3 NM_021023.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.77

Genes affected

CFHR3 (HGNC:16980): (complement factor H related 3) The protein encoded by this gene is a secreted protein, which belongs to the complement factor H-related protein family. It binds to heparin, and may be involved in complement regulation. Mutations in this gene are associated with decreased risk of age-related macular degeneration, and with an increased risk of atypical hemolytic-uremic syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008396715).
• BP6: Variant 1-196774939-G-C is Benign according to our data. Variant chr1-196774939-G-C is described in ClinVar as [Benign]. Clinvar id is 774281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196774939-G-C is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 44 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFHR3	NM_021023.6	c.53G>C	p.Gly18Ala	missense_variant	1/6	ENST00000367425.9
CFHR3	NM_001166624.2	c.53G>C	p.Gly18Ala	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFHR3	ENST00000367425.9	c.53G>C	p.Gly18Ala	missense_variant	1/6	1	NM_021023.6	P1
CFHR3	ENST00000471440.6	c.53G>C	p.Gly18Ala	missense_variant	1/5	1
CFHR3	ENST00000391985.7	c.53G>C	p.Gly18Ala	missense_variant	1/5	2
CFHR3	ENST00000367427.7	c.53G>C	p.Gly18Ala	missense_variant, NMD_transcript_variant	1/7	5

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 239 AN: 136504 Hom.: 44 Cov.: 25

Gnomad AFR AF: 0.000946

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000712

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00891

Gnomad FIN AF: 0.000296

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00260

Gnomad OTH AF: 0.00110

GnomAD3 exomes AF: 0.00298 AC: 711 AN: 238240 Hom.: 154 AF XY: 0.00365 AC XY: 469 AN XY: 128446

Gnomad AFR exome AF: 0.000879

Gnomad AMR exome AF: 0.000325

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0147

Gnomad FIN exome AF: 0.000236

Gnomad NFE exome AF: 0.00251

Gnomad OTH exome AF: 0.00154

GnomAD4 exome AF: 0.00339 AC: 4715 AN: 1389992 Hom.: 850 Cov.: 29 AF XY: 0.00375 AC XY: 2592 AN XY: 690432

Gnomad4 AFR exome AF: 0.000290

Gnomad4 AMR exome AF: 0.000413

Gnomad4 ASJ exome AF: 0.0000823

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0133

Gnomad4 FIN exome AF: 0.000382

Gnomad4 NFE exome AF: 0.00329

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.00175 AC: 239 AN: 136628 Hom.: 44 Cov.: 25 AF XY: 0.00162 AC XY: 108 AN XY: 66520

Gnomad4 AFR AF: 0.000943

Gnomad4 AMR AF: 0.0000711

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00891

Gnomad4 FIN AF: 0.000296

Gnomad4 NFE AF: 0.00260

Gnomad4 OTH AF: 0.00108

Alfa AF: 0.00205 Hom.: 8

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00302 AC: 25

ExAC AF: 0.00327 AC: 378

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Atypical hemolytic-uremic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.092
DEOGEN2	Benign	0.035	T;T;.;T
Eigen	Benign	0.066
Eigen_PC	Benign	-0.084
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.53	T;.;T;T
MetaRNN	Benign	0.0084	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.;M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.0	N;N;N;.
REVEL	Benign	0.16
Sift	Benign	1.0	T;T;T;.
Sift4G	Benign	0.94	T;T;T;T
Polyphen		0.85	P;D;.;.
Vest4		0.39
MVP		0.35
MPC		0.14
ClinPred		0.046	T
GERP RS		2.4
Varity_R		0.066
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs140313679; hg19: chr1-196744069;